Squamous cell carcinoma of the oral cavity (OSCC) is a devastating disease that is strongly associated with tobacco use. While OSCC most commonly occurs in tobacco users, there are many tobacco users who do not develop carcinoma. The factors that cause some tobacco users to develop OSCC, while others do not, are poorly studied to date. It can be theorized that some smokers are inherently more susceptible to developing carcinoma when exposed to carcinogens. This may be due to patterns of tobacco use, innate metabolism of carcinogens, or altered excretion. Identifying those smokers who are most at-risk for the development of OSCC would have great benefit through pre-diagnosis clinical surveillance. The proposed research project aims to identify differences between smokers with and without OSCC as a method to understand carcinogenesis and risk in those cigarette smokers who develop carcinoma. One approach to better understand the extent of exposure to, and metabolism of, tobacco carcinogens is through the study of tobacco carcinogen exposure markers. Levels of tobacco carcinogen exposure markers can be assayed in the urine to identify patterns of dose, exposure and metabolism. The objective of this proposal is to determine which tobacco carcinogen exposure markers are most associated with tobacco-induced OSCC through a case-control study. Cases will consist of smokers with OSCC and controls will be smokers who do not have OSCC. The exposure markers we will study are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'- nitrosonornicotine (NNN), 1-hydroxypyrene and cotinine. In addition, we will also study the formation of DNA adducts in buccal squamous cells. Given that DNA adducts can lead to mutagenesis and eventually carcinoma, investigating their distribution in OSCC patients represents a unique effort to identify carcinogenic pathways in smoking-induced OSCC. Our central hypothesis is that smokers with OSCC will have higher urinary exposure marker levels and higher mutagenic DNA adduct formation in oral squamous cells than smokers without OSCC. This proposal also includes a comprehensive mentoring and training plan for the primary investigator. Aspects of the training plan include didactic instruction in epidemiology, biostatistics and data analysis in addition to extensive training by the project mentors in laboratory techniques, study design, data analysis and grantsmanship. The ultimate goal of the mentoring proposed in this application is the eventual establishment of an independent research program by the primary investigator. In summary, this proposal seeks to identify tobacco carcinogen exposure markers and DNA adducts that are elevated in smokers with OSCC. This will form the foundation of an understanding of tobacco associated carcinogenesis and risk in OSCC and direct our future investigations in this area.